Medical Device Insertion

ABSTRACT

Devices and methods for inserting at least a portion of a medical device in a patient are provided. Embodiments include medical device insertions that employ a plurality of insertion stages. Also provided are systems and kits for use in analyte monitoring.

RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.11/617,698 filed Dec. 28, 2006, now U.S. Pat. No. 8,545,403, whichclaims priority under 35 USC §119 to Provisional Patent Application No.60/754,870 filed on Dec. 28, 2005, entitled “Medical Device Insertion”,the disclosures of each of which are incorporated herein by referencefor all purposes.

BACKGROUND

There are many instances in which it is necessary to position at least aportion of a medical device beneath the epidermis of a patient, e.g., inthe subcutaneous layer or elsewhere.

For example, the monitoring of the level of glucose or other analytes,such as lactate or oxygen or the like, in certain individuals is vitallyimportant to their health. The monitoring of glucose is particularlyimportant to individuals with diabetes, as they must determine wheninsulin is needed to reduce glucose levels in their bodies or whenadditional glucose is needed to raise the level of glucose in theirbodies.

In this regard, devices have been developed for continuous or automaticmonitoring of analytes, such as glucose, in the blood stream orinterstitial fluid. Many of these analyte measuring devices areconfigured so that at least a portion of the devices is positioned belowthe epidermis, e.g., in a blood vessel or in the subcutaneous tissue ofa patient.

These devices, as well as other medical devices, may be positionedmanually, e.g., by a user or a healthcare worker, or automatically orsemi-automatically with the aid of a sensor positioning device.Regardless of the manner in which the device is inserted beneath theskin, it is important that the device positioning process does notadversely affect the operation of the device. Furthermore, it isimportant that pain is minimal.

As interest in inserting medical devices, e.g., continuous analytemonitoring devices, beneath the epidermis of a patient continues, thereis interest in devices and methods for operably inserting such devices.Of interest are such devices and methods that have minimal impact ondevice function and which produce minimal pain. Of particular interestare continuous analyte monitoring positioning devices that enableclinically accurate analyte information to be obtained substantiallyimmediately following device positioning in a patient.

SUMMARY

Generally, the present invention relates to methods and devices forpositioning a medical device at least partially beneath the epidermallayer of skin. In certain embodiments, the present invention relates tothe continuous and/or automatic in vivo monitoring of the level of ananalyte using an analyte sensor and more specifically devices andmethods for operably positioning analyte sensors at least partiallybeneath the epidermal layer of skin. The subject invention is furtherdescribed with respect to positioning an analyte sensing device (alsoreferred to herein as a “sensor”, “analyte monitoring device/sensor”,and the like) and analyte sensing systems, where such description is inno way intended to limit the scope of the invention. It is understoodthat the subject invention is applicable to any medical device in whichat least a portion of the device is intended to be positioned beneaththe epidermis.

Embodiments of the subject invention include analyte sensor positioningdevices and methods that are adapted to provide clinically accurateanalyte data (e.g., analyte-related signal) substantially immediatelyafter a sensor has been operably positioned in a patient (e.g., at leasta portion of the sensor in the subcutaneous tissue, or elsewhere).

Embodiments of the subject invention include systems in which the periodof time after a sensor is positioned in a patient, when a first (oronly) sensor calibration is required, is substantially reduced(excluding any factory-set calibration) and/or the number ofcalibrations (excluding any factory-set calibration) is reduced, e.g.,to three or less calibrations, e.g., two or less calibrations, e.g., onecalibration or no calibrations.

Also provided are sensor positioning devices and methods that at leastminimize, and in many instances eliminate, the occurrence of periods ofspurious, low analyte readings, e.g., substantially immediatelyfollowing sensor positioning, during the night, etc.

Embodiments include devices and methods that modulate the sensorpositioning speed, or otherwise the rate at which a sensor is deliveredto a site in a patient, e.g., using at least two different velocities.

Also provided are positioning devices and methods that operably positiona sensor in a site of a patient using an acute angle, relative to theskin.

Embodiments also include sensor positioning devices and methods thatemploy an anesthetic agent.

Aspects include minimal pain, including substantially pain-free, sensorpositioning methods and devices and sensor positioning methods anddevices that do not substantially interfere with sensor function.

Also provided are systems and kits.

BRIEF DESCRIPTION OF THE DRAWINGS

The invention may be more completely understood in consideration of thefollowing detailed description of various embodiments of the inventionin connection with the accompanying drawings, in which:

FIG. 1 shows a block diagram of an exemplary embodiment of an analytemonitor using an implantable analyte sensor, according to the invention;

FIG. 2 is a top view of one embodiment of an analyte sensor, accordingto the invention;

FIG. 3A is a cross-sectional view of the analyte sensor of FIG. 2;

FIG. 3B is a cross-sectional view of another embodiment of an analytesensor, according to the invention;

FIG. 4A is a cross-sectional view of another embodiment of an analytesensor, according to the invention;

FIG. 4B is a cross-sectional view of a fourth embodiment of anotherembodiment of a sensor, according to the invention;

FIG. 5 is a cross-sectional view of another embodiment of an analytesensor, according to the invention;

FIG. 6 is an expanded top view of a tip-portion of the analyte sensor ofFIG. 2;

FIG. 7 is an expanded bottom view of a tip-portion of the analyte sensorof FIG. 2;

FIG. 8 is a side view of the analyte sensor of FIG. 2;

FIG. 9 is a cross-sectional view of an embodiment of an on-skin sensorcontrol unit, according to the invention;

FIG. 10 is a top view of a base of an on-skin sensor control unit;

FIG. 11 is a bottom view of a cover of an on-skin sensor control unit;

FIG. 12 is a perspective view of an on-skin sensor control unit on theskin of a patient;

FIG. 13A is a block diagram of one embodiment of an on-skin sensorcontrol unit, according to the invention;

FIG. 13B is a block diagram of another embodiment of an on-skin sensorcontrol unit, according to the invention;

FIG. 14 is a block diagram of one embodiment of a receiver/display unit,according to the invention;

FIG. 15 is an expanded view of an exemplary embodiment of a sensor and asensor positioning device, according to the invention;

FIGS. 16A, 16B, 16C are cross-sectional views of three embodiments ofthe insertion device of FIG. 15;

FIG. 17 is a perspective view of the internal structure of an exemplaryembodiment of an insertion device;

FIGS. 18A-18B are a front component view and perspective view,respectively, of the two stage sensor insertion mechanism in accordancewith one embodiment of the present invention;

FIG. 19A illustrates a front component view of the two stage sensorinsertion mechanism after the activation of the first stage triggerbutton to achieve the initial puncture in accordance with one embodimentof the present invention;

FIGS. 19B-19D illustrate a perspective view, a close-up perspectiveview, and a side view, respectively, of the two stage sensor insertionmechanism after the first stage trigger button activation shown in FIG.19A, where the side view shown in FIG. 19D further illustrates therelationship of the carrier and drive spring with the plunger and thetrigger button in one embodiment of the present invention;

FIGS. 20A-20B illustrate the front component view and the perspectiveview, respectively, of the two stage sensor insertion mechanism afterthe sensor placement at the predetermined depth with the plungerdepressed down to deliver the sensor to the maximum predetermined depthin accordance with one embodiment of the present invention;

FIG. 21 illustrates a front perspective component view of the returnspring of the two stage sensor insertion mechanism to retract and/orretain the sensor introducer in a retracted position after sensorinsertion in accordance with one embodiment of the present invention;

FIGS. 22A-22D illustrate a two stage sensor insertion process with thesensor and the sensor introducer in a nested configuration in accordancewith one embodiment;

FIGS. 23A-23C is a close up view of the sensor and sensor introducer ina two stage sensor insertion process in a non-nested configuration inaccordance with one embodiment;

FIGS. 24A-24C illustrate a side view, a front view and a bottomperspective view, respectively, of the two stage sensor insertionmechanism assembly including a skin displacement module in accordancewith one embodiment;

FIGS. 25A-25C illustrate a side view, a front view and a bottomperspective view, respectively, of the two stage sensor insertionmechanism assembly including a skin displacement module in accordancewith another embodiment;

FIG. 26 is a graphical illustration of the experimental data obtainedusing a non-two stage sensor insertion mechanism; and

FIG. 27 is a graphical illustration of the experimental data obtainedusing a two stage sensor insertion approach in accordance with oneembodiment.

DEFINITIONS

Throughout the present application, unless a contrary intention appears,the following terms refer to the indicated characteristics.

A “biological fluid” or “physiological fluid” or “body fluid”, is anybody fluid in which an analyte can be measured, for example, blood,interstitial fluid, dermal fluid, sweat, tears, and urine. “Blood”includes whole blood and its cell-free components, such as, plasma andserum.

A “counter electrode” refers to an electrode paired with the workingelectrode, through which passes a current equal in magnitude andopposite in sign to the current passing through the working electrode.In the context of the invention, the term “counter electrode” is meantto include counter electrodes which also function as referenceelectrodes (i.e., a counter/reference electrode).

An “electrochemical sensor” is a device configured to detect thepresence and/or measure the level of an analyte in a sample viaelectrochemical oxidation and reduction reactions on the sensor. Thesereactions are transduced to an electrical signal that can be correlatedto an amount, concentration, or level of an analyte in the sample.

“Electrolysis” is the electrooxidation or electroreduction of a compoundeither directly at an electrode or via one or more electron transferagents.

A compound is “immobilized” on a surface when it is entrapped on orchemically bound to the surface.

A “non-leachable” or “non-releasable” compound or a compound that is“non-leachably disposed” is meant to define a compound that is affixedon the sensor such that it does not substantially diffuse away from theworking surface of the working electrode for the period in which thesensor is used (e.g., the period in which the sensor is implanted in apatient or measuring a sample).

Components are “immobilized” within a sensor, for example, when thecomponents are covalently, ionically, or coordinatively bound toconstituents of the sensor and/or are entrapped in a polymeric orsol-gel matrix or membrane which precludes mobility. For example, incertain embodiments an anesthetic agent or precursor thereof may beimmobilized within a sensor.

An “electron transfer agent” is a compound that carries electronsbetween the analyte and the working electrode, either directly, or incooperation with other electron transfer agents. One example of anelectron transfer agent is a redox mediator.

A “working electrode” is an electrode at which the analyte (or a secondcompound whose level depends on the level of the analyte) iselectrooxidized or electroreduced with or without the agency of anelectron transfer agent.

A “working surface” is that portion of the working electrode which iscoated with or is accessible to the electron transfer agent andconfigured for exposure to an analyte-containing fluid.

A “sensing layer” is a component of the sensor which includesconstituents that facilitate the electrolysis of the analyte. Thesensing layer may include constituents such as an electron transferagent, a catalyst which catalyzes a reaction of the analyte to produce aresponse at the electrode, or both. In some embodiments of the sensor,the sensing layer is non-leachably disposed in proximity to or on theworking electrode.

A “non-corroding” conductive material includes non-metallic materials,such as carbon and conductive polymers.

When one item is indicated as being “remote” from another, this isreferenced that the two items are at least in different buildings, andmay be at least one mile, ten miles, or at least one hundred milesapart. When different items are indicated as being “local” to each otherthey are not remote from one another (for example, they can be in thesame building or the same room of a building). “Communicating”,“transmitting” and the like, of information reference conveying datarepresenting information as electrical or optical signals over asuitable communication channel (for example, a private or publicnetwork, wired, optical fiber, wireless radio or satellite, orotherwise). Any communication or transmission can be between deviceswhich are local or remote from one another. “Forwarding” an item refersto any means of getting that item from one location to the next, whetherby physically transporting that item or using other known methods (wherethat is possible) and includes, at least in the case of data, physicallytransporting a medium carrying the data or communicating the data over acommunication channel (including electrical, optical, or wireless).“Receiving” something means it is obtained by any possible means, suchas delivery of a physical item. When information is received it may beobtained as data as a result of a transmission (such as by electrical oroptical signals over any communication channel of a type mentionedherein), or it may be obtained as electrical or optical signals fromreading some other medium (such as a magnetic, optical, or solid statestorage device) carrying the information. However, when information isreceived from a communication it is received as a result of atransmission of that information from elsewhere (local or remote).

When two items are “associated” with one another they are provided insuch a way that it is apparent that one is related to the other such aswhere one references the other.

Items of data are “linked” to one another in a memory when a same datainput (for example, filename or directory name or search term) retrievesthose items (in a same file or not) or an input of one or more of thelinked items retrieves one or more of the others.

It will also be appreciated that throughout the present application,that words such as “cover”, “base”, “front”, “back”, “top”, “upper”, and“lower” are used in a relative sense only.

“May” refers to optionally.

When two or more items (for example, elements or processes) arereferenced by an alternative “or”, this indicates that either could bepresent separately or any combination of them could be present togetherexcept where the presence of one necessarily excludes the other orothers.

Any recited method can be carried out in the order of events recited orin any other order which is logically possible. Reference to a singularitem, includes the possibility that there is a plurality of the sameitem present.

DETAILED DESCRIPTION

Before the present invention is described, it is to be understood thatthis invention is not limited to particular embodiments described, assuch may, of course, vary. It is also to be understood that theterminology used herein is for the purpose of describing particularembodiments only, and is not intended to be limiting, since the scope ofthe present invention will be limited only by the appended claims.

Where a range of values is provided, it is understood that eachintervening value, to the tenth of the unit of the lower limit unlessthe context clearly dictates otherwise, between the upper and lowerlimit of that range and any other stated or intervening value in thatstated range, is encompassed within the invention. That the upper andlower limits of these smaller ranges may independently be included inthe smaller ranges is also encompassed within the invention, subject toany specifically excluded limit in the stated range. Where the statedrange includes one or both of the limits, ranges excluding either orboth of those included limits are also included in the invention.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs. Although any methods andmaterials similar or equivalent to those described herein can also beused in the practice or testing of the present invention, the preferredmethods and materials are now described.

It must be noted that as used herein and in the appended claims, thesingular forms “a”, “an”, and “the” include plural referents unless thecontext clearly dictates otherwise.

As will be apparent to those of skill in the art upon reading thisdisclosure, each of the individual embodiments described and illustratedherein has discrete components and features which may be readilyseparated from or combined with the features of any of the other severalembodiments without departing from the scope or spirit of the presentinvention.

The figures shown herein are not necessarily drawn to scale, with somecomponents and features being exaggerated for clarity.

As summarized above, the present invention is related to analyte sensorpositioning devices and methods (the term “positioning” is used hereininterchangeably with “delivery”, “insertion”, and the like). The presentinvention is applicable to an analyte monitoring system using asensor—at least a portion of which is positionable beneath the skin ofthe user for the in vivo determination of a concentration of an analyte,such as glucose, lactate, and the like, in a body fluid. The sensor maybe, for example, subcutaneously positionable in a patient for thecontinuous or periodic monitoring of an analyte in a patient'sinterstitial fluid. This may be used to infer the glucose level in thepatient's bloodstream. The sensors of the subject invention also includein vivo analyte sensors insertable into a vein, artery, or other portionof the body containing fluid. A sensor of the subject invention istypically configured for monitoring the level of the analyte over a timeperiod which may range from minutes, hours, days, weeks, or longer. Ofinterest are analyte sensors, such as glucose sensors, that are capableof providing analyte data for about one hour or more, e.g., about a fewhours or more, e.g., about a few days of more, e.g., about three or moredays, e.g., about five days or more, e.g., about seven days or more,e.g., about several weeks or months.

Embodiments include positioning devices and systems, and methods thatprovide clinically accurate analyte data (e.g., relative to a reference)substantially immediately, as shown by any suitable technique known tothose of skill in the art, e.g., a Clark Error Grid, Parks Error Grid,Continuous Glucose Error Grid, MARD analysis, and the like. For example,in those embodiments in which the sensor is a continuous sensor and atleast a portion of the sensor is adapted to be positioned under the skinof a patient, the sensor is adapted to provide clinically accurateanalyte data (e.g., relative to a reference) substantially immediatelyafter the sensor is operably positioned in a patient. In other words,the waiting period from the time a sensor is positioned in a user andthe time clinically accurate data may be obtained and used by the user,is greatly reduced relative to prior art devices that require a greaterwaiting period before accurate analyte data may be obtained and used bya user. By “substantially immediately” is meant from about 0 hours toless than about 5 hours, e.g., from about 0 hours to about 3 hours,e.g., from about 0 hours to less than about 1 hour, e.g., from about 30minutes or less, where in many embodiments the sensors according to thesubject invention are capable of providing clinically accurate analytedata once the sensor has been operatively positioned in the patient.

As noted above, embodiments also include analyte monitoring devices andmethods having substantially reduced (including eliminated) periods oftime of spurious, low analyte readings, as compared to a control, i.e.,the period of time in which clinically accurate analyte data isobtainable is greater, as compared to a control. The subject inventionmay be employed to minimize or eliminate spurious low analyte readingsobtained at any time during sensor use, including a period of timeimmediately after sensor activation (e.g., positioning of an analytesensor in or on a patient) and/or anytime thereafter. Accordingly,embodiments include sensor positioning devices and methods that enablesensors to provide clinically accurate analyte data substantiallyimmediately after the sensor has been operably positioned in a patient(e.g., in the subcutaneous tissue, etc.) and/or without substantialinterruption due to spurious analyte readings

Embodiments include minimal tissue trauma-producing analyte positioningdevices and methods, where embodiments include modulating the rate atwhich a sensor is delivered to a target site. For example, at least twovelocities may be used in the positioning of a sensor, where embodimentsinclude a multiple rate sensor delivery protocol having a first sensordelivery rate, followed by a second sensor delivery rate that is lessthan the first. Embodiments may include opening the skin with a firstvelocity, and inserting the sensor through the thus-formed skin openingto a target site (e.g., into the subcutaneous tissue) with a second,minimal tissue trauma-producing velocity, where the second velocity isless than the first velocity. Such may be accomplished automatically orsemi-automatically with a sensor positioning device. The positioningdevice may include a sharp portion and a sensor-carrying portion and maybe adapted to provide a skin incision and position a sensor in a patientusing variable speeds. It is to be understood that such may beaccomplished wholly or at least partially manually.

Certain embodiments include two-stage sensor delivery devices andmethods and include devices capable of producing, for example, first andsecond velocities, each associated with a respective one of thetwo-stages of the sensor delivery devices and methods. Alternatively,one or more properties associated with the sensor delivery procedure maycorrespond respectively to each of the two stage sensor delivery devicesand methods, and which may include, for example, incision angles andincision depth in addition to or in lieu of the first and secondvelocities corresponding to the two stages of sensor delivery.

Specific embodiments include devices capable of producing a superficialcut in the skin that may be no deeper than the epidermis, oralternatively no deeper than the dermis, using a first velocity, andinserting the sensor through the thus-formed cut to a target site usinga second velocity that is slower than the first velocity. The speed ofthe first velocity may be selected to minimize the patient's perceptionof pain and the speed of the second velocity may be selected to minimizetissue damage at the site of eventual glucose measurements. For example,the high speed of the first velocity (e.g., from about 4 to about 8 m/sin certain embodiments) may minimize the patient's pain while the slowerspeed of the second velocity (e.g., from about 0.025 to about 0.5 m/s incertain embodiments) may minimize the damage due to the tissue at thesite of the eventual glucose sensor measurements. Accordingly, a usercontacts the device to a skin surface and actuates the device to cut theskin and insert the sensor through the cut to the target site, using atleast two different velocities for the incision forming and sensordelivery operations.

The various velocities employed may differ by any suitable amount. Forexample, in certain embodiments in which two velocities are employed,the velocities may differ by about 25% to about 95%, e.g., by about 60%to about 90%. Velocity change may be gradual or stepped. The change invelocity may be perceptible to the user or not, where in manyembodiments the velocity change is not perceptible by the user. Incertain embodiments, the sensor positioning process is automatic in thata user need only activate the device, e.g., actuate a button, lever,contact with a skin surface, or the like, to initiate the sensorpositioning process, the process then proceeds to completion without anyfurther user intervention. In some embodiments one or more parametersmay be user configurable such as, for example, the timing of velocitychange, magnitudes of one or more velocities, one or more angles ofinsertion or incision, relative location of the insertion needle to thesensor for transcutaneous placement, incision or insertion depth underthe skin layer, or combinations thereof.

Embodiments of the above-described two-speed sensor insertion minimizetissue damage to the site of the final analyte sensor placement in thesubcutaneous adipose tissue layer. By limiting the depth of the incisionto the upper layers of the skin, i.e., the stratum corneum andepidermis, minimization of tissue damage at the site of the eventualanalyte sensor placement in the subcutaneous adipose tissue layer may beachieved. The application of greater penetration forces, and hence agreater likelihood of tissue damage, may be limited to the upper layersof the skin, distant from the site of the final analyte sensor placementin the subcutaneous adipose tissue layer.

Furthermore, since in certain embodiments a separate sharp is notemployed to penetrate below the outer layer of skin, not only is thetissue damage in the subcutaneous adipose layer minimized by use of theslower speed in the second velocity portion of the insertion, but thephysical size and dimension of the wound is greatly reduced byeliminating the use of a separate sharp device penetrating below theouter layer of the skin.

In certain embodiments, the sharp device which disrupts the stratumcorneum and epidermis may penetrate from about 0.5 mm to about 1.5 mmbelow the surface of the skin. In certain analyte sensing systems, theanalyte-sensing chemistry layer on the sensor, by contrast, may bepositioned below or deeper than this penetration, e.g., below about 0.5mm to about 1.5 mm below the surface of the skin. The slow speed of thesecond velocity portion of the insertion displaces the adipose cells inthe subcutaneous adipose tissue layer rather than physically disruptingthe cells and effectively coring out a cylinder in which the sensor maybe subsequently placed. In the present invention, the slow speed of thesecond velocity portion of the insertion minimizes the volume of tissuewhich has been removed or even displaced by the sensor insertion. As aresult, the sensing portion of the sensor is in immediate proximalcontact with the surrounding tissue. In contrast to typical insertionmethods in which a cylindrical core of tissue is displaced or removed bya high-speed insertion, in the present invention there is no open volumeof tissue in which fluids may accumulate forming edema typical of woundresponse to trauma of this nature. The absence of or the significantreduction of edema in the present invention associated with theminimization of the perturbed volume of tissue contributes to rapidsensor equilibration with the method of sensor insertion describedherein compared with conventional sensor insertion procedures.

Embodiments include making a large wide cut through the epidermis, thena much smaller incision in terms of its cross-sectional dimensionsthrough the dermis and into the underlying subcutaneous adipose tissuelayer, where in certain embodiments as much as about a fourfolddifference in the cross-sectional area (e.g., 0.48 mm² for the incisionin the epidermis compared to 0.12 mm² for the incision in thesubcutaneous layer).

The subject invention also includes anesthetic agents in sensorpositioning. That is, certain embodiments include sensor positioningdevices, methods and/or sensors that include an anesthetic agent(“active agent”). The active agent may be any suitable anestheticagent(s) known or to be discovered. Examples of anesthetic agentsinclude, but are not limited to, lidocaine (with or withoutepinephrine), prilocalne, bupivacaine, benzocaine, and ropivacaine,marcaine (with or without epiniephrine) and the like, and combinationsthereof, as well as cold sprays such as ethyl chloride sprays.

The active-agent containing devices may be analyte sensors and/oranalyte sensor positioning devices in certain embodiments, and/or may bea structure that is positionable near a skin location site at which sitean incision is or will be made and sensor is or will be inserted (a bodyfluid sampling site). In certain embodiments, the structure may be asensor positioning device, drug delivery device (e.g., insulin deliverydevice), etc.

In certain embodiments, active agent may not be carried by a device, butrather may be otherwise applied at or substantially near the sensorinsertion site. Accordingly, embodiments include systems having anactive agent delivery unit and an analyte sensor.

Active agent employed in the subject invention may be deliveredtransdermally, by a topical route, formulated as applicator sticks,solutions, suspensions, emulsions, gels, creams, ointments, pastes,jellies, paints, powders, and aerosols. For example, embodiments mayinclude an active agent in the form of a discrete patch or film orplaster or the like adapted to remain in intimate contact with theepidermis of the recipient for a period of time. For example, suchtransdermal patches may include a base or matrix layer, e.g., polymericlayer, in which active agent is retained. The base or matrix layer maybe operably associated with a support or backing Active agents suitablefor transdermal administration may also be delivered by iontophoresisand may take the form of an optionally buffered aqueous solution thatincludes the active agent. Suitable formulations may include citrate orbis/tris buffer (pH 6) or ethanol/water and contain a suitable amount ofactive ingredient.

Active agents may be applied via parenteral administration, such asintravenous (“IV”) administration, intramuscular (“IM”), subcutaneous(“SC” or “SQ”), mucosal. The formulations for such administration mayinclude a solution of the active agent dissolved in a pharmaceuticallyacceptable carrier. Among the acceptable vehicles and solvents that maybe employed, include, but are not limited to, water and Ringer'ssolution, an isotonic sodium chloride, etc. Active agent may beformulated into preparations for injection by dissolving, suspending oremulsifying them in an aqueous or nonaqueous solvent, such as vegetableor other similar oils, synthetic aliphatic acid glycerides, esters ofhigher aliphatic acids or propylene glycol; and if desired, withconventional additives such as solubilizers, isotonic agents, suspendingagents, emulsifying agents, stabilizers and preservatives. Thesesolutions are sterile and generally free of undesirable matter.

In other embodiments, the active agent may be delivered by the use ofliposomes which fuse with the cellular membrane or are endocytosed,i.e., by employing ligands attached to the liposome, or attacheddirectly to the oligonucleotide, that bind to surface membrane proteinreceptors of the cell resulting in endocytosis. By using liposomes,particularly where the liposome surface carries ligands specific fortarget cells, or are otherwise preferentially directed to a specificorgan, one can focus the delivery of the pharmacological agent into thetarget cells in vivo. (See, e.g., Al-Muhammed, J. Microencapsul.13:293-306, 1996; Chonn, Curr. Opin. Biotechnol. 6:698-708, 1995; Ostro,Am. J. Hosp. Pharm. 46:1576-1587, 1989). Methods for preparing liposomalsuspensions are known in the art and thus will not be described hereinin great detail.

Embodiments may also include administration of active agent using anactive agent administration device other than a sensor positioningdevice and a sensor such as, but not limited to, pumps (implantable orexternal devices and combinations of both (e.g., certain components maybe implantable and others may be external to the body such as controlsfor the implantable components)), epidural injectors, syringes or otherinjection apparatus, catheter and/or reservoir operably associated witha catheter, etc. For example, in certain embodiments a device employedto deliver active agent to a subject may be a pump, syringe, catheter orreservoir operably associated with a connecting device such as acatheter, tubing, or the like. Containers suitable for delivery ofactive agent to an active agent administration device includeinstruments of containment that may be used to deliver, place, attach,and/or insert the active agent into the delivery device foradministration of the active agent to a subject and include, but are notlimited to, vials, ampules, tubes, capsules, bottles, syringes and bags.Embodiments may also include administration of active agent via abiodegradable implant active agent delivery device. Such may beaccomplished by employing syringes to deposit such a biodegradabledelivery device under the skin of a subject. The implants degradecompletely, so that removal is not necessary.

Embodiments may include employing an electrode to deliver active agentto a subject. For example, an electrode may be used that has a smallport at its tip which is connected to a reservoir or pump containingactive agent. The active agent delivery electrode may be implanted usingany suitable technique such as surgical cut down, laproscopy, endoscopy,percutaneous procedure, and the like. In certain embodiments a reservoiror pump may also be implanted in the subject's body. The active agentdelivery electrode, or other analogous device, may be controllable suchthat the amount of active agent delivered, the rate at which the activeagent may be delivered, and the time period over which the active agentmay be delivered, etc., may be controllable and may be adjusted, e.g.,by a user and/or healthcare worker.

Accordingly, embodiments include contacting an analyte determinationsite with active agent, and determining the concentration of an analyte,where the contacting may be by way of an analyte sensor, analyte sensorpositioning device or other structure, transdermal administration,parenteral administration, etc.

In those embodiments in which a sensor positioning device and/or sensoror other device includes active agent, the active agent-containingstructure may include or incorporate active agent in any suitablemanner. For example, at least a portion of a positioning device and/orsensor, e.g., a body fluid-contacting portion, may include active agent,where in certain embodiments substantially the entire positioning deviceand/or sensor may include active agent. Active agent may be immobilizedon a surface of a positioning device and/or sensor or may be configuredto diffuse away from a surface of a positioning device and/or sensor. Incertain embodiments, at least the portion of the positioning device thatis adapted to provide a skin incision, e.g., a sharp of a sensorpositioning device, may include active agent.

In certain embodiments, active agent is a coating on at least a portionof positioning device and/or sensor. In certain embodiments, activeagent is incorporated, e.g., embedded, or otherwise integrated into apositioning device and/or sensor.

A positioning device and/or sensor may also have the ability to emit ordiffuse active agent at a controllable rate, e.g., may include acontrolled release, such as a time release, formulation. For example, apositioning device and/or sensor may include a formulation that isdesigned to release active agent gradually over time, e.g., over about aperiod of time commensurate with sensor positioning. A controlledrelease formulation may employ a polymer or other non-anesthetic agentmaterial to control the release of the active agent. The active agentrelease rate may be slowed by diffusion through the polymer, or theactive agent may be released as the polymer degrades or disintegrates inthe body.

The active agent may be added to a positioning device and/or sensorduring fabrication thereof and/or may be applied after fabrication. Forexample, a coating containing active agent thereof may be applied to apositioning device and/or sensor after it has been fabricated.

Active agent may be applied to a positioning device and/or sensor by anyof a variety of methods, e.g., by spraying the active agent onto atleast a portion of a positioning device and/or sensor or by dipping apositioning device and/or sensor into the active agent, or otherwiseimmersing or flooding a positioning device and/or sensor with the activeagent.

The amount of active agent employed may vary depending on a variety offactors such as the particular active agent used, the particulars of thepositioning device and/or sensor, etc. In any event, an effective amountof active agent is used—an amount sufficient to provide the requisiteanesthetic result for the desired period of time.

Representative analyte sensors, analyte monitoring systems and sensorpositioning devices are now described, where such description is forexemplary purposes only and is in no way intended to limit the scope ofthe invention.

Analyte Sensors and Sensor Systems

The analyte sensors and analyte monitoring systems of the presentinvention can be utilized under a variety of conditions. The particularconfiguration of a sensor and other units used in an analyte monitoringsystem may depend on the use for which the sensor and system areintended and the conditions under which the sensor and system willoperate. As noted above, embodiments include a sensor configured forimplantation into a patient or user. The term “implantation” is meantbroadly to include wholly implantable sensors and sensors in which onlya portion of which is implantable under the skin and a portion of whichresides above the skin, e.g., for contact to a transmitter, receiver,transceiver, processor, etc. For example, implantation of the sensor maybe made in the arterial or venous systems for direct testing of analytelevels in blood. Alternatively, a sensor may be implanted in theinterstitial tissue for determining the analyte level in interstitialfluid. This level may be correlated and/or converted to analyte levelsin blood or other fluids. The site and depth of implantation may affectthe particular shape, components, and configuration of the sensor.Subcutaneous implantation may be desired, in some cases, to limit thedepth of implantation of the sensor. Sensors may also be implanted inother regions of the body to determine analyte levels in other fluids.Examples of suitable sensors for use in the analyte monitoring systemsof the invention are described in U.S. Pat. Nos. 6,134,461, 6,175,752,and elsewhere.

An exemplary embodiment of an analyte monitoring system 40 for use withan implantable sensor 42, e.g., for use with a subcutaneouslyimplantable sensor, is illustrated in block diagram form in FIG. 1. Theanalyte monitoring system 40 includes, at minimum, a sensor 42, at leasta portion of the sensor which is configured for implantation (e.g.,subcutaneous, venous, or arterial implantation) into a patient, and asensor control unit 44. The sensor 42 is coupleable to the sensorcontrol unit 44 which is typically attachable to the skin of a patient.The sensor control unit 44 operates the sensor 42, including, forexample, providing a voltage across the electrodes of the sensor 42 andcollecting signals from the sensor 42.

The sensor control unit 44 may evaluate the signals from the sensor 42and/or transmit the signals to one or more optional receiver/displayunits 46, 48 for evaluation. The sensor control unit 44 and/or thereceiver/display units 46, 48 may display or otherwise communicate thecurrent level of the analyte. Furthermore, the sensor control unit 44and/or the receiver/display units 46, 48 may indicate to the patient,via, for example, an audible, visual, or other sensory-stimulatingalarm, when the level of the analyte is at or near a threshold level. Insome embodiments, an electrical shock may be delivered to the patient asa warning through one of the electrodes or the optional temperatureprobe of the sensor. For example, if glucose is monitored then an alarmmay be used to alert the patient to a hypoglycemic or hyperglycemicglucose level and/or to impending hypoglycemia or hyperglycemia.

A sensor 42 includes at least one working electrode 58 and a substrate50, as shown in FIG. 2. The sensor 42 may also include at least onecounter electrode 60 (or counter/reference electrode) and/or at leastone reference electrode 62 (see for example FIG. 7). The counterelectrode 60 and/or reference electrode 62 may be formed on thesubstrate 50 or may be separate units. For example, the counterelectrode and/or reference electrode may be formed on a second substratewhich is also implantable in the patient or, for some embodiments of thesensors, the counter electrode and/or reference electrode may be placedon the skin of the patient with the working electrode or electrodesbeing implanted into the patient. The use of an on-the-skin counterand/or reference electrode with an implantable working electrode isdescribed in, e.g., U.S. Pat. No. 5,593,852.

The working electrode or electrodes 58 are formed using conductivematerials 56. The counter electrode 60 and/or reference electrode 62, aswell as other optional portions of the sensor 42, such as a temperatureprobe 66 (see for example, FIG. 7), may also be formed using conductivematerial 56. The conductive material 56 may be formed over a smoothsurface of the substrate 50 or within channels 54 formed by, forexample, embossing, indenting or otherwise creating a depression in thesubstrate 50.

A sensing layer 64 (see for example FIGS. 3, 4, 5 and 6) may be providedproximate to or on at least one of the working electrodes 58 tofacilitate the electrochemical detection of the analyte and thedetermination of its level in the sample fluid, particularly if theanalyte cannot be electrolyzed at a desired rate and/or with a desiredspecificity on a bare electrode.

In addition to the electrodes 58, 60, 62 and the sensing layer 64, thesensor 42 may also include optional components such as one or more ofthe following: a temperature probe 66 (see for example FIGS. 5 and 7), amass transport limiting layer 74, e.g., a matrix such as a membrane orthe like, (see for example FIG. 8), a biocompatible layer 75 (see forexample FIG. 8), and/or other optional components, as described below.Each of these optional items enhances the functioning of and/or resultsfrom the sensor 42, as discussed below.

The substrate 50 may be formed using a variety of non-conductingmaterials, including, for example, polymeric or plastic materials andceramic materials. Suitable materials for a particular sensor 42 may bedetermined, at least in part, based on the desired use of the sensor 42and properties of the materials.

In addition to considerations regarding flexibility, it is oftendesirable that a sensor 42 should have a substrate 50 which isnon-toxic. Preferably, the substrate 50 is approved by one or moreappropriate governmental agencies or private groups for in vivo use.Although the substrate 50 in at least some embodiments has uniformdimensions along the entire length of the sensor 42, in otherembodiments, the substrate 50 has a distal end 67 and a proximal end 65with different widths 53, 55, respectively, as illustrated in FIG. 2.

At least one conductive trace 52 may be formed on the substrate for usein constructing a working electrode 58. In addition, other conductivetraces 52 may be formed on the substrate 50 for use as electrodes (e.g.,additional working electrodes, as well as counter, counter/reference,and/or reference electrodes) and other components, such as a temperatureprobe. The conductive traces 52 may extend most of the distance along alength 57 of the sensor 42, as illustrated in FIG. 2, although this isnot necessary. The placement of the conductive traces 52 may depend onthe particular configuration of the analyte monitoring system (e.g., theplacement of control unit contacts and/or the sample chamber in relationto the sensor 42). For implantable sensors, particularly subcutaneouslyimplantable sensors, the conductive traces may extend close to the tipof the sensor 42 to minimize the amount of the sensor that must beimplanted.

The conductive traces may be formed using a conductive material 56 suchas carbon (e.g., graphite), a conductive polymer, a metal or alloy(e.g., gold or gold alloy), or a metallic compound (e.g., rutheniumdioxide or titanium dioxide), and the like. Conductive traces 52 (andchannels 54, if used) may be formed with relatively narrow widths. Inembodiments with two or more conductive traces 52 on the same side ofthe substrate 50, the conductive traces 52 are separated by distancessufficient to prevent conduction between the conductive traces 52. Theworking electrode 58 and the counter electrode 60 (if a separatereference electrode is used) may be made using a conductive material 56,such as carbon.

The reference electrode 62 and/or counter/reference electrode may beformed using conductive material 56 that is a suitable referencematerial, for example silver/silver chloride or a non-leachable redoxcouple bound to a conductive material, for example, a carbon-bound redoxcouple.

The electrical contact 49 may be made using the same material as theconductive material 56 of the conductive traces 52 or alternatively, maybe made from a carbon or other non-metallic material, such as aconducting polymer.

A number of exemplary electrode configurations are described below,however, it will be understood that other configurations may also beused. In certain embodiments, e.g., illustrated in FIG. 3A, the sensor42 includes two working electrodes 58 a, 58 b and one counter electrode60, which also functions as a reference electrode. In anotherembodiment, the sensor includes one working electrode 58 a, one counterelectrode 60, and one reference electrode 62, as shown for example inFIG. 3B. Each of these embodiments is illustrated with all of theelectrodes formed on the same side of the substrate 50.

Alternatively, one or more of the electrodes may be formed on anopposing side of the substrate 50. In another embodiment, two workingelectrodes 58 and one counter electrode 60 are formed on one side of thesubstrate 50 and one reference electrode 62 and a temperature probe 66are formed on an opposing side of the substrate 50, as illustrated inFIG. 6. The opposing sides of the tip of this embodiment of the sensor42 are illustrated in FIGS. 6 and 7.

Some analytes, such as oxygen, may be directly electrooxidized orelectroreduced on the working electrode 58. Other analytes, such asglucose and lactate, require the presence of at least one electrontransfer agent and/or at least one catalyst to facilitate theelectrooxidation or electroreduction of the analyte. Catalysts may alsobe used for those analytes, such as oxygen, that can be directlyelectrooxidized or electroreduced on the working electrode 58. For theseanalytes, each working electrode 58 has a sensing layer 64 formedproximate to or on a working surface of the working electrode 58. Inmany embodiments, the sensing layer 64 is formed near or on only a smallportion of the working electrode 58, e.g., near a tip of the sensor 42.

The sensing layer 64 includes one or more components designed tofacilitate the electrolysis of the analyte. The sensing layer 64 may beformed as a solid composition of the desired components (e.g., anelectron transfer agent and/or a catalyst). These components may benon-leachable from the sensor 42 and may be immobilized on the sensor42. For example, the components may be immobilized on a workingelectrode 58. Alternatively, the components of the sensing layer 64 maybe immobilized within or between one or more membranes or films disposedover the working electrode 58 or the components may be immobilized in apolymeric or sol-gel matrix. Examples of immobilized sensing layers aredescribed in, e.g., U.S. Pat. Nos. 5,262,035; 5,264,104; 5,264,105;5,320,725; 5,593,852; and 5,665,222; and PCT Patent Application No.US98/02403 entitled “Soybean Peroxidase Electrochemical Sensor”.

Sensors having multiple working electrodes 58 a may also be used, e.g.,and the signals therefrom may be averaged or measurements generated atthese working electrodes 58 a may be averaged. In addition, multiplereadings at a single working electrode 58 a or at multiple workingelectrodes may be averaged.

In many embodiments, the sensing layer 64 contains one or more electrontransfer agents in contact with the conductive material 56 of theworking electrode 58, as shown for example in FIGS. 3 and 4 and 5.Useful electron transfer agents and methods for producing them aredescribed in, e.g., U.S. Pat. Nos. 5,264,104; 5,356,786; 5,262,035;5,320,725; 6,175,752; 6,329,161; and elsewhere.

The sensing layer 64 may also include a catalyst which is capable ofcatalyzing a reaction of the analyte. The catalyst may also, in someembodiments, act as an electron transfer agent.

To electrolyze the analyte, a potential (versus a reference potential)is applied across the working and counter electrodes 58, 60. When apotential is applied between the working electrode 58 and the counterelectrode 60, an electrical current will flow.

Those skilled in the art will recognize that there are many differentreactions that will achieve the same result; namely the electrolysis ofan analyte or a compound whose level depends on the level of theanalyte.

A variety of optional items may be included in the sensor. One optionalitem is a temperature probe 66 (see for example FIG. 7). One exemplarytemperature probe 66 is formed using two probe leads 68, 70 connected toeach other through a temperature-dependent element 72 that is formedusing a material with a temperature-dependent characteristic. An exampleof a suitable temperature-dependent characteristic is the resistance ofthe temperature-dependent element 72. The temperature probe 66 canprovide a temperature adjustment for the output from the workingelectrode 58 to offset the temperature dependence of the workingelectrode 58.

The sensors of the subject invention are biocompatible. Biocompatibilitymay be achieved in a number of different manners. For example, anoptional biocompatible layer 75 may be formed over at least that portionof the sensor 42 which is inserted into the patient, as shown in FIG. 8.

An interferant-eliminating layer (not shown) may be included in thesensor 42. The interferant-eliminating layer may include ioniccomponents, such as Nafion® or the like, incorporated into a polymericmatrix to reduce the permeability of the interferant-eliminating layerto ionic interferants having the same charge as the ionic components.

A mass transport limiting layer 74 may be included with the sensor toact as a diffusion-limiting barrier to reduce the rate of mass transportof the analyte, for example, glucose or lactate, into the region aroundthe working electrodes 58. Exemplary layers that may be used aredescribed for example, in U.S. Pat. No. 6,881,551, and elsewhere.

A sensor of the subject invention may be adapted to be a replaceablecomponent in an in vivo analyte monitor, and particularly in animplantable analyte monitor. As described above, in many embodiments thesensor is capable of operation over a period of days or more, e.g., aperiod of operation may be at least about one day, e.g., at least aboutthree days, e.g., at least about five days, e.g., at least about oneweek or more, e.g., one month or more. The sensor may then be removedand replaced with a new sensor.

As described above, sensor positioning devices are provided. Embodimentsof the subject positioning devices include low impact, minimalpain-producing devices, where certain embodiments are configured toobtain clinically accurate analyte information substantially immediatelyafter sensor positioning. Device embodiments include variable insertionspeed devices. Embodiments of the two stage sensor inserters describedherein include single use, disposable, self-contained Sensor DeliveryUnits (“SDU”) which may be included in a continuous glucose monitoringsystem.

Referring to FIG. 15, sensor positioning device 120 may be used toinsert, e.g., subcutaneously insert, at least a portion of the sensor 42into the patient. The sensor positioning device 120 may be formed usingstructurally rigid materials, such as metal or rigid plastic. Exemplarymaterials include, but are not limited to, stainless steel and ABS(acrylonitrile-butadiene-styrene) plastic. In some embodiments, thesensor positioning device 120 is pointed and/or sharp at the tip 121 tofacilitate penetration of the skin of the patient. A sharp, thin sensorpositioning device may reduce pain felt by the patient upon insertion ofthe sensor 42. In other embodiments, the tip 121 of the sensorpositioning device 120 has other shapes, including a blunt or flatshape. These embodiments may be particularly useful when the sensorpositioning device 120 does not penetrate the skin but rather serves asa structural support for the sensor 42 as the sensor 42 is pushed intothe skin. In embodiments in which at least a portion of the positioningdevice includes an anesthetic agent, such may be included in anysuitable location of device 120, e.g., at least a portion of tip 121.

The sensor positioning device 120 may have a variety of cross-sectionalshapes, as shown in FIGS. 16A, 16B, and 16C. The sensor positioningdevice 120 illustrated in FIG. 16A is a flat, planar, pointed strip ofrigid material which may be attached or otherwise coupled to the sensor42 to ease insertion of the sensor 42 into the skin of the patient, aswell as to provide structural support to the sensor 42 during insertion.The sensor positioning devices 120 of FIGS. 16B and 16C are U- orV-shaped implements that support the sensor 42 to limit the amount thatthe sensor 42 may bend or bow during insertion. The cross-sectionalwidth 124 of the sensor positioning devices 120 illustrated in FIGS. 16Band 16C may be about 1 mm or less, e.g., about 700 μm or less, e.g.,about 500 μm or less, e.g., about 300 μm or less. The cross-sectionalheight 126 of the sensor positioning device 120 illustrated in FIGS. 16Band 16C may be about 1 mm or less, e.g., about 700 μm or less, e.g.,about 500 μm or less in certain embodiments.

The sensor 42 may include optional features to facilitate insertion. Forexample, the sensor 42 may be pointed at the tip 123 to ease insertion,as illustrated in FIG. 15. In addition, the sensor 42 may include a barb125 which helps retain the sensor 42 in the subcutaneous tissue of thepatient. The barb 125 may also assist in anchoring the sensor 42 at thetarget site, e.g., within the subcutaneous tissue, of the patient duringoperation of the sensor 42. However, the barb 125 is typically smallenough that little damage is caused to the subcutaneous tissue when thesensor 42 is removed for replacement. The sensor 42 may also include anotch 127 that can be used in cooperation with a corresponding structure(not shown) in the sensor positioning device to apply pressure againstthe sensor 42 during insertion, but disengage as the sensor positioningdevice 120 is removed. One example of such a structure in the sensorpositioning device is a rod (not shown) between two opposing sides of asensor positioning device 120 and at an appropriate height of the sensorpositioning device 120.

In operation, a sensor is carried by the positioning device to thetarget site. For example, the sensor 42 is placed within or next to thesensor positioning device 120 (e.g., may be partially or completely heldwithin the sharp of the device, e.g., in a nested configuration or thelike) and then a force is provided against the sensor positioning device120 and/or sensor 42 to carry the sensor 42 into the skin of thepatient. As described above, in certain embodiments various speeds maybe used in a given insertion, e.g., a first speed followed by a secondspeed where the first speed is greater relative to the second speed.

In one embodiment, the force is applied to the sensor 42 to push thesensor into the skin, while the sensor positioning device 120 remainsstationary and provides structural support to the sensor 42.Alternatively, the force is applied to the sensor positioning device 120and optionally to the sensor 42 to push a portion of both the sensor 42and the sensor positioning device 120 through the skin of the patientand into the subcutaneous tissue. In any event, the forces used may bethe same or different, as noted herein. The sensor positioning device120 is optionally pulled out of the skin and subcutaneous tissue withthe sensor 42 remaining in the subcutaneous tissue due to frictionalforces between the sensor 42 and the patient's tissue. If the sensor 42includes the optional barb 125, then this structure may also facilitatethe retention of the sensor 42 within the interstitial tissue as thebarb catches in the tissue. The force applied to the sensor positioningdevice 120 and/or the sensor 42 may be applied manually or mechanically.The sensor 42 is reproducibly inserted through the skin of the patient.

In certain embodiments, an insertion gun may be used to insert thesensor. One example of an insertion gun 200 for inserting a sensor 42 isshown in FIG. 17. The insertion gun 200 includes a housing 202 and acarrier 204. The sensor positioning device 120 is typically mounted onthe carrier 204 and the sensor 42 is pre-loaded into the sensorpositioning device 120. The carrier 204 drives the sensor 42 and,optionally, the sensor positioning device 120 into the skin of thepatient using, for example, a cocked or wound spring, a burst ofcompressed gas, an electromagnet repelled by a second magnet, or thelike, within the insertion gun 200. In some instances, for example, whenusing a spring, the carrier 204 and sensor positioning device may bemoved, cocked, or otherwise prepared to be directed towards the skin ofthe patient.

After the sensor 42 is inserted, the insertion gun 200 may contain amechanism which pulls the sensor positioning device 120 out of the skinof the patient. Such a mechanism may use a spring, electromagnet, or thelike to remove the sensor positioning device 120.

The insertion gun may be reusable. The sensor positioning device 120 isoften disposable to avoid the possibility of contamination.Alternatively, the sensor positioning device 120 may be sterilized andreused. In addition, the sensor positioning device 120 and/or the sensor42 may be coated with an anticlotting agent to prevent fouling of thesensor 42.

In one embodiment, the sensor 42 is injected between about 2 to about 12mm into the interstitial tissue of the patient for subcutaneousimplantation, e.g., the sensor is injected about 3 to about 9 mm, e.g.,about 5 to about 7 mm, into the interstitial tissue. Other embodimentsof the invention may include sensors implanted in other portions of thepatient, including, for example, in an artery, vein, or organ. The depthof implantation varies depending on the desired implantation target. Inany event, in certain embodiments the injection is at a speed thatdiffers from the speed employed to create an opening in the skin throughwhich the sensor is injected.

Although the sensor 42 may be inserted anywhere in the body, it is oftendesirable that the insertion site be positioned so that the on-skinsensor control unit 44 may be concealed. In addition, it is oftendesirable that the insertion site be at a place on the body with a lowdensity of nerve endings to reduce the pain to the patient. Examples ofpreferred sites for insertion of the sensor 42 and positioning of theon-skin sensor control unit 44 include the abdomen, thigh, leg, upperarm, and shoulder.

Any suitable angle of insertion may be used. An insertion angle ismeasured from the plane of the skin (i.e., inserting the sensorperpendicular to the skin would be a 90 degree insertion angle). Asnoted herein, in certain embodiments an angle less than about 90 degreesis used. The orientation of the two stage or two speed sensor inserterdevice may be either at normal angle to the skin or at an oblique angleto the skin such as but not limited to about 20, about 25, about 30,about 45 or about 60 degrees with respect to the skin surface itself. Incontrast with the sensor used in the case of normal or 90 degreeinsertion, in instances in which other angles are used, the length ofthe sensor itself may be adjusted by standard trigonometric relations sothat the actual depth of placement remains the same (e.g., remainscomparable to that achieved using a 90 degree angle), e.g., in certainembodiments about 5.0 mm below the surface of the skin, i.e. in themidst of the subcutaneous adipose tissue layer.

The use of an angled insertion (i.e. less than about 90 degrees relativeto the skin) in the present achieves physical separation of thesuperficial incision from the position in the tissue at which the sensorwill be measuring the analyte of interest. Furthermore, the use ofangled insertion may decrease the physical displacement of the sensoritself relative to the subcutaneous adipose tissue layer when physicalpressure is applied to the sensor mount and transmitter in the course ofa patient's normal daily living. This may be especially important forminimizing the occurrences of spurious low readings during periods ofsleep.

The use of an angled insertion in the present invention takes advantageof the stratum corneum's reduced susceptibility to shear disruption orpenetration compared with rupture due to direct normal insertion. Lessforce is required to penetrate the stratum corneum and the epidermisusing an angled insertion than an insertion conducted at normalincidence. The latter may be accompanied by greater degrees of damagedue to the underlying tissue as well as the release of various chemicalmessengers active in the wound response of the epidermis and dermis.

Embodiments also include devices and methods for determining thethickness of the subcutaneous adipose tissue layer in a given individualat a given anatomical site such as the lower left or right abdominalquadrant or the posterior or lateral upper arm. Such devices and/oralgorithms may be integrated with a positioning device or may beseparate. For example, in the event that the subcutaneous adipose tissuelayer at the desired location for the placement of the sensor is lessthan or approximately equal to a predetermined amount, e.g., about 5.0mm, sensor lengths and/or angles which correctly place the activeglucose transduction area of the sensor in the middle of the targetedsubcutaneous adipose tissue layer may be determined and used.

Sensor positioning devices may involve manual, semi-automatic, orautomatic operation, referring to the origin of the force that is usedboth to insert the sensor and to retract any portion of the sensorpositioning device out of the skin of the patient that is not intendedto remain inserted during the period of sensor operation. Semi-automaticor automatic operation refers to the incorporation of one or moreforce-generating methods, e.g., wound springs, compressed gas,electromagnet repulsion of a second magnet, and the like, either incombination with manual force or replacing manual force entirely, forthe purpose of inserting the sensor and/or retracting any portion of thesensor positioning device out of the skin of the patient that is notintended to remain inserted during the period of sensor operation.

In certain embodiments, a plunger-type button is used as the actuationmechanism of an insertion gun. The button serves the purpose ofreleasing a compressed spring that drives the sharp tip of the sensorpositioning device into the skin of the patient at a fast speed,consistent with minimizing pain, so as to create a superficial skinincision that may be no deeper than the epidermis. The sharp tip of thepositioning device may then be refracted out of the skin of the patient,manually or using a mechanism such as a spring, electromagnet, or thelike. The continued travel of the actuator button would then also servethe purpose of manually driving the sensor into the skin, through theincision created by the sharp tip of the positioning device, at avelocity less than that used to create the incision.

In certain other embodiments of the device, the insertion gun includes ahousing and a carrier. The sensor positioning device is typicallymounted on the carrier and the sensor is pre-loaded into the sensorpositioning device. The carrier drives the sensor positioning deviceinto the skin of the patient using, for example, a cocked or woundspring, a burst of compressed gas, an electromagnet repelled by a secondmagnet, and the like, within the insertion gun. The velocity of thecarrier may be decreased, after the creation of the superficial skinincision, through mechanical means e.g., viscous dashpots, air damping,friction, the addition of mass to the carrier, or the like. Thecontinued motion of the carrier, for the purpose of inserting the sensorinto the incision created by the sharp tip of the positioning device,would then occur at a velocity less than that used to create theincision. The sharp tip of the positioning device may be retracted outof the skin of the patient, either after the creation of the skinincision or after sensor insertion, manually or using a mechanism suchas a spring, electromagnet, or the like.

Embodiments include a two stage or two velocity sensor inserter devicethat includes a base, housing, carrier/introducer/sensor assembly, highspeed activation button, drive spring, return spring and manual plunger.These inserters may be provided to users fully assembled and armed witha sensor enclosed inside the introducer.

In use, the first stage of the insertion may begin by activating thedevice, e.g., by pressing the plunger and activation button, to causethe introducer to be propelled into the skin at a higher rate of speedthan the speed that will be used at the second stage. The introducermakes a “shallow puncture”, but does not release the sensor.

The “shallow puncture” depth may be controlled by the height andlocation of the latch ledge features on the housing, or the type andforce (rate) of the drive spring or in other ways such as hard stop,increase of friction, magnets, safety lock, or dial (similar to a lancetdevice), and the like. The “shallow puncture” or superficial incisionmay not provide a channel into which the glucose sensor is placed, butrather may provide an opening in the upper layer of the skin.

After the “shallow puncture” or superficial incision is made through thestratum corneum and epidermis, the return spring retracts the sharpportion of the introducer out of the skin. The overall (uncompressed)height of the return spring positions the introducer/sensor slightlyabove the surface of the skin (puncture) for the second stage of theinsertion.

When the first stage is activated (releasing the latches of the carriermechanism), the high speed button comes to rest in a lower position ontop of the housing, thereby leaving the plunger in the “up” and readyposition. The introducer having made the puncture is now in the “next”position (with the sensor still intact).

The second stage of the insertion may be accomplished manually (e.g.,similar to and approximately as slow or slower than injection viasyringe) by the user. Pressing down on the plunger causes theintroducer/carrier/sensor to move from the “next” position and continueinto the shallow puncture until the prescribed sensor insertion depth isreached. The prescribed insertion depth may be controlled by thecompressed (solid) height of the return spring or in some other way suchas hard stop, adhesive mount, safety lock or other similar restrainingor limiting device.

When the prescribed depth is reached, the sensor body may be captured byfeatures on an adhesive mount mounted on the patient's skin and releasedfrom the introducer for contact with the transmitter which isconnectable to the mount. The insertion is complete when the first phasehas provided an opening through the outer layer of the skin and thesecond phase has resulted in the placement of the sensor at the desireddepth in the subcutaneous adipose tissue layer.

The user releases the plunger (e.g., by removing their finger) and thereturn spring causes the introducer to exit the skin and into the “safefor disposal position”. The SDU may then be detached from the mount anddiscarded accordingly.

A sensor insertion such as described above may be accomplished with onehand and without the benefit of direct line of sight.

The two stage insertion process may be achieved in one motion, (e.g., bythe user pressing the top of the plunger and pushing down until it comesto rest on the top of the housing). However, the user may make a “2motion-2 stage” insertion (by pressing the plunger, stopping after thehigh speed button has been activated then pressing the plunger).

FIGS. 18A-18B are a front component view and perspective view,respectively, of the two stage sensor insertion mechanism including theinsertion device armed and ready for insertion, further illustrating thesensor introducer and sensor to make the first stage puncture, and alsoshowing the plunger and the button in accordance with one embodiment ofthe present invention. Referring to the Figures, the two stage sensorinsertion mechanism 1800 in one embodiment may include a button 1801operatively coupled to a plunger 1802. Also shown in the Figures aresensor introducer 1803 and sensor 1804.

As shown in the Figures, in one embodiment, the plunger 1802 may beoperatively coupled to the introducer 1803 by a carrier 1806, where theintroducer 1803 is further operatively coupled to the sensor 1804. Inone aspect, the activation of the button 1801 may be configured todisplace the plunger 1802 substantially in the direction as shown byarrow 1805 such that the carrier 1806 is likewise displaced in thedirection of the arrow 1805, which in turn, is configured tocorrespondingly displace the sensor 1804 and the sensor introducer 1803substantially in the same direction.

FIG. 19A illustrates a front component view of the two stage sensorinsertion mechanism after the activation of the first stage triggerbutton to achieve the initial puncture, and with the plunger exposed forthe second stage insertion activation, and also illustrating thesensor/introducer position after the initial first stage puncture (forexample, at 1.55 mm depth) in accordance with one embodiment of thepresent invention. FIGS. 19B-19D illustrate a perspective view, aclose-up perspective view, and a side view, respectively, of the twostage sensor insertion mechanism after the first stage trigger buttonactivation shown in FIG. 19A, where the side view shown in FIG. 19Dfurther illustrates the relationship of the carrier 1806 and drivespring 1901 with the plunger 1802 and the trigger button 1801. FIGS.20A-20B illustrate the front component view and the perspective view,respectively, of the two stage sensor insertion mechanism after thesensor placement at the predetermined depth with the plunger depresseddown to deliver the sensor to the maximum predetermined depth inaccordance with one embodiment of the present invention.

FIG. 21 illustrates a front perspective component view of the returnspring of the two stage sensor insertion mechanism to retract and/orretain the sensor introducer in a retracted position after sensorinsertion in accordance with one embodiment of the present invention.More particularly, in one aspect, the spring 1901 may be configured toretract or remove the introducer from the puncture site after sensordeployment to the predetermined depth.

FIGS. 22A-22D illustrate a two stage sensor insertion process with thesensor and the sensor introducer in a nested configuration in accordancewith one embodiment. Referring to FIGS. 22A-22B, in one embodiment, aportion of the sensor 1804 is substantially nested in at least a portionof the introducer 1803 such that the movement of the introducer 1803also displaces the sensor 1804. Accordingly, in one embodiment, duringthe first stage of the sensor insertion, the introducer 1803 and thesensor 1804 are propelled into the skin at a first predetermined speedor velocity through skin layer 2201. The introducer 1803 makes a shallowpuncture and positions the tip or end portion of the tail (or distal)segment of the sensor 1804 as well as the sharp end portion of theintroducer 1803 at a first predetermined depth 2202 (for example, in thesubcutaneous adipose tissue layer) which is less than the desired orfinal depth of the sensor 1804 to be positioned. In one embodiment, theleading tip (sharp end) of the introducer 1803 is at substantially thesame length or extends beyond the length of the sensor tail segment 1804to facilitate the skin puncture or incision generated by the introducer1803, and further to minimize the pain during the initial puncture orincision on the skin layer 2201.

Referring now to FIGS. 22C and 22D, during the second stage of thesensor insertion, the introducer 1803 is removed from the skin layer andwholly retracted from the patient or may be maintained at the firstpredetermined depth 2202, while the sensor 1804 is further displaced tothe second and final predetermined depth 2203 so as to position the tipor tail segment of the sensor 1804 at the final target depth 2203 in thesubcutaneous adipose tissue layer. In one embodiment, the second stageinsertion of the sensor 1804 as described herein may be achievedmanually, semi-automatically or automatically by the user or patient.For example, as described below in conjunction with FIGS. 24A-24C, and25A-25C, the two stage insertion mechanism may be provided with a skindisplacement module coupled to the introducer 1803, or alternatively,coupled to the two stage insertion mechanism assembly. Alternatively, ina further embodiment, the patient or the user may manually press down orotherwise apply force upon the skin of the patient so as to translatethe downward force upon the sensor that is positioned at the firstpredetermined depth 2202 such that the applied force may position thesensor 1804 at the final desired depth 2203 under the skin layer 2201.

FIGS. 23A-23C is a close up view of the sensor and sensor introducer ina two stage sensor insertion process in a non-nested configuration inaccordance with one embodiment. Referring to FIGS. 23A-23C, in oneembodiment, the two stage sensor insertion mechanism is employed topierce the skin 2303 using the introducer 1803 to create a puncture orincision. Thereafter, the introducer 1803 is removed, and the sensor1804 is inserted through the puncture or incision created by theintroducer 1803. In one aspect, the introducer 1803 may be configured tocreate the incision in the superficial layers of the skin such that whenthe introducer 1803 is removed, it leaves behind an opening in the skinalong with a region of traumatized tissue 2301. When the sensor 1804 issubsequently inserted through the opening in the skin created by theintroducer 1803, the inserted portion (or the tip or tail segment) ofthe sensor 1804 which has a smaller cross sectional area than the sharptip of the introducer 1803 may be inserted through the region of thetraumatized tissue 2301 to a greater depth (2302) in the skin layer2303. In this manner, in one embodiment, the wound or tissue trauma inthe local vicinity of the distal tip (or tail segment) of the sensor1804 may be minimized.

In the manner described above, in accordance with the variousembodiments of the present invention, the accuracy of sensor values maybe increased by minimizing tissue trauma and associated inflammatorycells substantially surrounding the transcutaneously positioned sensor1804.

FIGS. 24A-24C illustrate a side view, a front view and a bottomperspective view, respectively, of the two stage sensor insertionmechanism assembly including a skin displacement module in accordancewith one embodiment, and FIGS. 25A-25C illustrate a side view, a frontview and a bottom perspective view, respectively, of the two stagesensor insertion mechanism assembly including a skin displacement modulein accordance with another embodiment of the present invention.

As discussed above, in one embodiment, the sensor insertion deviceassembly 2400, 2500 may include a skin displacement module 2401, 2501which may be configured to press upon and apply a predetermined pressureupon the skin layer of the patient when the sensor insertion deviceassembly 2400, 2500 is placed on the patient or user's skin. In oneembodiment, the module 2401 may be provided on the bottom portion of theinsertion assembly, for example, as a protrusion, such that theplacement of the bottom portion of the insertion assembly presses uponthe skin layer beyond the base or bottom portion of the insertionassembly. In another embodiment, the module 2501 may be provided on aportion of the introducer that is not pierced through the skin layer ofthe user or the patient. In this manner, when the module is retracted orpositioned relative to the skin surface so as to not apply pressurethereupon, the skin will return substantially to its original nondepressed position, and which, in turn, allows the sensor 1804 to bepositioned at the final depth in the skin (as the sensor 1804 ismaintained in the same position during this process relative to thepatient or the user's skin).

In this manner, the skin displacement module 2401, 2501 may beconfigured to compress the skin prior to or concurrent with the sensorinsertion and capture during the first stage of the sensor insertionprocess such that the skin is displaced from its relaxed height orthickness, to reduce the depth of puncture of the introducer 1803(relative to the plane of the uncompressed or relaxed skin layer).Thereafter, with the removal or retraction of the skin displacementmodule 2401, 2501, the compressed skin may be allowed to rebound orrecover to its uncompressed state, which in turn, allows the tip or tailsegment of the sensor 1804 to be positioned into previously unpuncturedsubcutaneous adipose tissue in a substantially minimally traumaticmanner at a rate of speed that is less than the rate of the speed atwhich the initial skin puncture with the introducer 1803 is created.Furthermore, while the skin displacement module 2401, 2501 shown in theFigures include the particular physical dimensions as shown in theFigures relative to the introducer 1803 and/or the sensor insertionassembly, within the scope of the present invention, other suitabletypes of mechanical and/or physical modules or devices may be providedso as to temporarily apply the desired pressure upon the skin layer ofthe patient or the user.

In the manner described, in accordance with one embodiment of thepresent invention, there is provided a multi-stage sensor insertionmethod and device, where the first stage of the sensor insertion isassociated with the initial puncture or incision of the skin layer,while the second or subsequent stage of the sensor insertion isassociated with the positioning of the sensor in the desired locationunder the skin of the patient or the user. In this manner, the second orsubsequent stage of the sensor insertion is substantially configured tominimize tissue trauma, including both initiation of inflammatoryresponse and rupture of microcapillaries.

The multi-stage sensor insertion in accordance with the variousembodiments of the present invention may include different insertionvelocities or speeds of the sensor introducer and the sensor, differentinsertion angles as between the insertion stages of the sensorintroducer and the sensor, the relative configuration of the introducerwith respect to the sensor, such as nested or non-nested configurationsas described above, and the like. Moreover, within the scope of thepresent invention, the stratum corneum may be incised at an angle(relative to the skin surface) which would require relatively less forcedue to the shear strength properties of the epidermis, and followed bythe sensor insertion a normal incidence to the skin surface.

Referring back to FIG. 1, the on-skin sensor control unit 44 isconfigured to be placed on the skin of a patient. One embodiment of theon-skin sensor control unit 44 has a thin, oval shape to enhanceconcealment, as illustrated in FIGS. 9-11. However, other shapes andsizes may be used. The on-skin sensor control unit 44 includes a housing45, as illustrated in FIGS. 9-11. The on-skin sensor control unit 44 istypically attachable to the skin 75 of the patient, as illustrated inFIG. 12. Another method of attaching the housing 45 of the on-skinsensor control unit 44 to the skin 75 includes using a mounting unit 77.

The sensor 42 and the electronic components within the on-skin sensorcontrol unit 44 are coupled via conductive contacts 80. The one or moreworking electrodes 58, counter electrode 60 (or counter/referenceelectrode), optional reference electrode 62, and optional temperatureprobe 66 are attached to individual conductive contacts 80. In theillustrated embodiment of FIGS. 9-11, the conductive contacts 80 areprovided on the interior of the on-skin sensor control unit 44.

Referring back to the Figures, the on-skin sensor control unit 44 mayinclude at least a portion of the electronic components that operate thesensor 42 and the analyte monitoring device system 40. One embodiment ofthe electronics in the on-skin control unit 44 is illustrated as a blockdiagram in FIG. 13A. The electronic components of the on-skin sensorcontrol unit 44 may include a power supply 95 for operating the on-skincontrol unit 44 and the sensor 42, a sensor circuit 97 for obtainingsignals from and operating the sensor 42, a measurement circuit 96 thatconverts sensor signals to a desired format, and a processing circuit109 that, at minimum, obtains signals from the sensor circuit 97 and/ormeasurement circuit 96 and provides the signals to an optionaltransmitter 98. In some embodiments, the processing circuit 109 may alsopartially or completely evaluate the signals from the sensor 42 andconvey the resulting data to the optional transmitter 98 and/or activatean optional alarm system 94 (see FIG. 13B) if the analyte level exceedsa threshold. The processing circuit 109 often includes digital logiccircuitry.

The on-skin sensor control unit 44 may optionally contain a transmitteror transceiver 98 for transmitting the sensor signals or processed datafrom the processing circuit 109 to a receiver (or transceiver)/displayunit 46, 48; a data storage unit 102 for temporarily or permanentlystoring data from the processing circuit 109; a temperature probecircuit 99 for receiving signals from and operating a temperature probe66; a reference voltage generator 101 for providing a reference voltagefor comparison with sensor-generated signals; and/or a watchdog circuit103 that monitors the operation of the electronic components in theon-skin sensor control unit 44.

Moreover, the sensor control unit 44 may include a bias controlgenerator 105 to correctly bias analog and digital semiconductordevices, an oscillator 107 to provide a clock signal, and a digitallogic and timing component to provide timing signals and logicoperations for the digital components of the circuit.

FIG. 13B illustrates a block diagram of another exemplary on-skin sensorcontrol unit 44 that also includes optional components such as areceiver (or transceiver) 110 to receive, for example, calibration data;a calibration data storage unit 102 to hold, for example, factory-setcalibration data, calibration data obtained via the receiver 110 and/oroperational signals received, for example, from a receiver/display unit46, 48 or other external device; an alarm system 94 for warning thepatient; and a deactivation switch 111 to turn off the alarm system.

The electronics in the on-skin sensor control unit 44 and the sensor 42are operated using a power supply 95. The sensor control unit 44 mayalso optionally include a temperature probe circuit 99.

The output from the sensor circuit 97 and optional temperature probecircuit is coupled into a measurement circuit 96 that obtains signalsfrom the sensor circuit 97 and optional temperature probe circuit 99and, at least in some embodiments, provides output data in a form that,for example can be read by digital circuits.

In some embodiments, the data from the processing circuit 109 isanalyzed and directed to an alarm system 94 (see FIG. 13B) to warn theuser.

In some embodiments, the data (e.g., a current signal, a convertedvoltage or frequency signal, or fully or partially analyzed data) fromprocessing circuit 109 is transmitted to one or more receiver/displayunits 46, 48 using a transmitter 98 in the on-skin sensor control unit44. The transmitter has an antenna 93, such as a wire or similarconductor, formed in the housing 45.

In addition to a transmitter 98, an optional receiver 110 may beincluded in the on-skin sensor control unit 44. In some cases, thetransmitter 98 is a transceiver, operating as both a transmitter and areceiver. The receiver 110 of the on-skin sensor control unit (and/orreceiver display/units 46, 48) may be used to receive calibration datafor the sensor 42. The calibration data may be used by the processingcircuit 109 to correct signals from the sensor 42. This calibration datamay be transmitted by the receiver/display unit 46, 48 or from someother source such as a control unit in a doctor's office.

Calibration data may be obtained in a variety of ways. For instance, thecalibration data may simply be factory-determined calibrationmeasurements which can be input into the on-skin sensor control unit 44using the receiver 110 or may alternatively be stored in a calibrationdata storage unit 102 within the on-skin sensor control unit 44 itselfor elsewhere such as, e.g., receiver display/units 46, 48, (in whichcase a receiver 110 may not be needed). The calibration data storageunit 102 may be, for example, a readable or readable/writeable memorycircuit.

Alternative or additional calibration data may be provided based ontests performed by a doctor or some other professional or by the patienthimself. For example, it is common for diabetic individuals to determinetheir own blood glucose concentration using commercially availabletesting kits. The result of this test is input into the on-skin sensorcontrol unit 44 (and/or receiver display/units 46, 48) either directly,if an appropriate input device (e.g., a keypad, an optical signalreceiver, or a port for connection to a keypad or computer) isincorporated in the on-skin sensor control unit 44, or indirectly byinputting the calibration data into the receiver/display unit 46, 48 andtransmitting the calibration data to the on-skin sensor control unit 44.

Other methods of independently determining analyte levels may also beused to obtain calibration data. This type of calibration data maysupplant or supplement factory-determined calibration values.

In some embodiments of the invention, calibration data may be requiredat periodic intervals, for example, about every ten hours, eight hours,about once a day, or about once a week, to confirm that accurate analytelevels are being reported. Calibration may also be required each time anew sensor 42 is implanted or if the sensor exceeds a threshold minimumor maximum value or if the rate of change in the sensor signal exceeds athreshold value. In some cases, it may be necessary to wait a period oftime after the implantation of the sensor 42 before calibrating to allowthe sensor 42 to achieve equilibrium. In some embodiments, the sensor 42is calibrated only after it has been inserted. In other embodiments, nocalibration of the sensor 42 is needed (e.g., a factory calibration maybe sufficient).

Regardless of the type of analyte monitoring system employed, it hasbeen observed that transient, low readings may occur for a period oftime. These anomalous low readings may occur during the first hours ofuse, or anytime thereafter. In certain embodiments, spurious lowreadings may occur during the night and may be referred to as “nighttime dropouts”. For example, in the context of an operably positionedcontinuous monitoring analyte sensor under the skin of a user, suchspurious low readings may occur for a period of time following sensorpositioning and/or during the first night post-positioning. In manyinstances, the low readings resolve after a period of time. However,these transient, low readings put constraints on analyte monitoringduring the low reading period. Attempts to address this problem vary andinclude delaying calibration and/or reporting readings to the user untilafter this period of low readings passes after positioning of the sensoror frequent calibration of the sensor—both of which are inconvenient andneither of which is desirable.

However, as noted above embodiments of the subject invention have atleast a minimal period, if at all, of spurious low readings, i.e., asubstantially reduced sensor equilibration period, includingsubstantially no equilibration period. In this regard, in thoseembodiments in which an initial post-positioning calibration isrequired, such may be performed substantially immediately after sensorpositioning. For example, in certain embodiments a calibration protocolmay include a first post-positioning calibration at less than about 10hours after a sensor has been operably positioned, e.g., less than about5 hours, e.g., less than about 3 hours, e.g., less than about 1 hour,e.g., less than about 0.5 hours. One or more additional calibrations maynot be required, or may be performed at suitable times thereafter.

The on-skin sensor control unit 44 may include an optional data storageunit 102 which may be used to hold data (e.g., measurements from thesensor or processed data).

In some embodiments of the invention, the analyte monitoring device 40includes only an on-skin control unit 44 and a sensor 42.

One or more receiver/display units 46, 48 may be provided with theanalyte monitoring device 40 for easy access to the data generated bythe sensor 42 and may, in some embodiments, process the signals from theon-skin sensor control unit 44 to determine the concentration or levelof analyte in the subcutaneous tissue. The receiver may be atransceiver. Receivers may be palm-sized and/or may be adapted to fit ona belt or within a bag or purse that the patient carries.

The receiver/display units 46, 48, as illustrated in block form at FIG.14, typically include a receiver 150 to receive data from the on-skinsensor control unit 44, an analyzer 152 to evaluate the data, a display154 to provide information to the patient, and an alarm system 156 towarn the patient when a condition arises. The receiver/display units 46,48 may also optionally include a data storage device 158, a transmitter160, and/or an input device 162.

Data received by the receiver 150 is then sent to an analyzer 152.

The output from the analyzer 152 is typically provided to a display 154.The receiver/display units 46, 48 may also include a number of optionalitems such as a data storage unit 158 store data, a transmitter 160which can be used to transmit data, and an input device 162, such as akeypad or keyboard.

In certain embodiments, the receiver/display unit 46, 48 is integratedwith a calibration unit (not shown). For example, the receiver/displayunit 46, 48 may, for example, include a conventional blood glucosemonitor. Devices may be used including those that operate using, forexample, electrochemical and colorimetric blood glucose assays, assaysof interstitial or dermal fluid, and/or non-invasive optical assays.When a calibration of the implanted sensor is needed, the patient usesthe integrated in vitro monitor to generate a reading. The reading maythen, for example, automatically be sent by the transmitter 160 of thereceiver/display unit 46, 48 to calibrate the sensor 42.

In certain embodiments, analyte data (processed or not) may be forwarded(such as by communication) to a remote location such as a doctor'soffice if desired, and received there for further use (such as furtherprocessing).

Integration with a Drug Administration System

The subject invention also includes sensors used in sensor-based drugdelivery systems. The system may provide a drug to counteract the highor low level of the analyte in response to the signals from one or moresensors. Alternatively, the system may monitor the drug concentration toensure that the drug remains within a desired therapeutic range. Thedrug delivery system may include one or more (e.g., two or more)sensors, a sensor positioning device, an on-skin sensor control unit, areceiver/display unit, a data storage and controller module, and a drugadministration system. In some cases, the receiver/display unit, datastorage and controller module, and drug administration system may beintegrated in a single unit. The sensor-based drug delivery system mayuse data from the one or more sensors to provide necessary input for acontrol algorithm/mechanism in the data storage and controller module toadjust the administration of drugs. As an example, a glucose sensorcould be used to control and adjust the administration of insulin.According to certain embodiments of the subject invention, accurate datafrom the one or more sensors may be obtained substantially immediatelyafter sensor positioning to provide necessary input for a controlalgorithm/mechanism in the data storage and controller module to adjustthe administration of drugs substantially immediately.

Kits

Finally, kits for use in practicing the subject invention are alsoprovided. The subject kits may include one or more sensors as describedherein. Embodiments may also include a sensor and/or a sensorpositioning device and/or transmitter and/or receiver and/or anestheticagent, which may or may not be independent of the sensor and/or sensorpositioning device.

In addition to one or more of the above-described components, thesubject kits may also include written instructions for using a sensor,e.g., positioning a sensor using a sensor positioning device and/orusing a sensor to obtain analyte information. The instructions may beprinted on a substrate, such as paper or plastic, etc. As such, theinstructions may be present in the kits as a package insert, in thelabeling of the container of the kit or components thereof (i.e.,associated with the packaging or sub-packaging) etc. In otherembodiments, the instructions are present as an electronic storage datafile present on a suitable computer readable storage medium, e.g.,CD-ROM, diskette, etc. In yet other embodiments, the actual instructionsare not present in the kit, but means for obtaining the instructionsfrom a remote source, e.g., via the Internet, are provided. An exampleof this embodiment is a kit that includes a web address where theinstructions can be viewed and/or from which the instructions can bedownloaded. As with the instructions, the means for obtaining theinstructions is recorded on a suitable substrate.

In many embodiments of the subject kits, the components of the kit arepackaged in a kit containment element to make a single, easily handledunit, where the kit containment element, e.g., box or analogousstructure, may or may not be an airtight container, e.g., to furtherpreserve the one or more sensors and additional reagents (e.g., controlsolutions), if present, until use.

The following examples are offered by way of illustration and not by wayof limitation.

EXPERIMENTAL

The following examples are put forth so as to provide those of ordinaryskill in the art with a complete disclosure and description of how tomake and use the present invention, and are not intended to limit thescope of what the inventors regard as their invention. Efforts have beenmade to ensure accuracy with respect to numbers used (e.g., amounts,temperature, etc.) but some experimental errors and deviations should beaccounted for. Unless indicated otherwise, parts are parts by weight,molecular weight is weight average molecular weight, temperature is indegrees Centigrade, and pressure is at or near atmospheric.

A clinical study was conducted to evaluate the effect of sensor deliveryapproaches to reduce the trauma associated with sensor insertion. Thesensor insertion included the placement of the working electrode,located on the distal tip of the sensor tail, in the subcutaneousadipose tissue layer at a depth of approximately 5.5 mm below thesurface of the skin. The initial skin incision was performed with theapplication of force upon the skin surface (through a spring-loadedinserter) and using a mechanical spacer such that the depth of thepuncture created by the introducer and of the initial depth of sensorplacement was reduced by approximately three millimeters from its targetdepth. Thereafter, the sensor and the introducer were delivered at apredetermined insertion speed. The mechanical spacer was then removedand light hand pressure was applied to the inserted sensor assembly (thetransmitter was positioned in the adhesive mount to fully engage thesensor within the adhesive mount) to cause the distal tip of the sensortail to reach its final placement depth. The tip of the introducerextends 2.5 millimeters beyond the tip of the inserted portion of thesensor such that the use of the applied pressure to manually positionthe sensor to a depth of 3 additional millimeters allowed the insertedtip of the sensor to be placed into approximately 0.5 millimeters ofpreviously unpunctured tissue. The rate of speed at which the finalplacement of the sensor was performed was less than the rate of speed atwhich the initial puncture was created.

No anesthetic was utilized during sensor insertions, and each subjectwore the two sensors concurrently on their lateral or posterior upperarms. A total of 71 successful sensor insertions were performed on 37subjects, yielding 67 evaluable datasets. Frequent reference bloodglucose measurements were obtained using blood glucose meters throughoutthe 72 hours of device usage. Performance was assessed using ClarkeError Grid Analysis and other standard statistical methods.

FIG. 26 is a graphical illustration of the experimental data obtainedusing a non-two stage sensor insertion mechanism. It can be seen that asmany as 8-10 hours of equilibration time may be required afterpositioning the sensor in a patient prior to providing clinicallyaccurate analyte information. Further, as shown, there is a relativelylow level of correlation between the continuous glucose sensor data andthe reference blood glucose values prior to approximately 8-10 hoursafter sensor insertion, but that after approximately 8-10 hours arelatively high level of correlation is achieved.

FIG. 27 is a graphical illustration of the experimental data obtainedusing a two stage sensor insertion approach in accordance with oneembodiment. It can be seen from FIG. 27, and compared to the resultsshown in FIG. 26, that there is a high level of correlation between thecontinuous glucose sensor data and the reference blood glucose valueswithin a short time following sensor positioning in a patient.

The effect of minimizing tissue damage to the site of the eventualanalyte sensor placement in the subcutaneous adipose tissue layer usinga two-speed insertion approach described above can be observed bycomparing the accuracy of data obtained from sensors during the first 24hours after sensor placement between two calibration schemes. The firstcalibration scheme (“standard cal”) involves calibration of thecontinuous glucose data to reference blood glucose measurements at 10,12, 24, and 72 hours after sensor placement. The second calibrationscheme (“expedited cal”) involves calibration of the continuous glucosedata to reference blood glucose measurements at 1, 3, 12, 24, and 72hours after sensor placement.

Analysis of data from the 67 evaluable data results indicated thatequivalent accuracy could be obtained in the first 24 hours after sensorinsertion using the expedited cal routine as compared to the standardcal routine. These results are summarized in the following table.

Accuracy Metric Standard Cal Expedited Cal Day 1 Mean ARD 14.3% 14.4%Day 1 Clarke A Zone 75.3% 75.3% N (paired continuous and reference data)582 1500

The above table demonstrates that a consistently high level of clinicalaccuracy of the glucose sensor can be maintained while substantiallydecreasing the time required prior to initial calibration andsignificantly increasing the amount of data available to device users inthe first 24 hours after sensor insertion using a two-stage insertionapproach designed to minimize tissue damage to the site of the eventualanalyte sensor placement in the subcutaneous adipose tissue layer.

It is evident from the above results and discussion that theabove-described invention provides devices and methods for continuousanalyte monitoring. The above-described invention provides a number ofadvantages some of which are described above and which include, but arenot limited to, minimal sensor positioning pain, minimal tissue traumafrom sensor positioning, the ability to provide clinically accurateanalyte data without a substantial time delay after operably positioningthe sensor in a patient or frequent calibrations, minimal, includingsubstantially no, periods of spurious analyte readings. As such, thesubject invention represents a significant contribution to the art.

A method of inserting an analyte sensor in one embodiment includespositioning a first portion of an analyte sensor at a firstpredetermined depth below a skin surface of a patient, and positioningthe first portion of the analyte sensor at a second predetermined depth,where the second predetermined depth is greater than the firstpredetermined depth.

The positioning of the first portion of the sensor at the firstpredetermined depth may include piercing the skin surface at a firstangle relative to the skin surface, where the first angle may includeone of a 90 degrees relative to the skin surface or less than 90 degreesrelative to the skin surface.

Also, the positioning first portion of the sensor at the firstpredetermined depth may include inserting the first portion of thesensor through the skin surface at a first velocity, where positioningthe first portion of the sensor at a second predetermined depth mayinclude inserting the first portion of the sensor at a second velocity.

The first velocity and the second velocity may be different.

A sensor insertion device in another embodiment may include a sensorintroducer configured to pierce through a skin layer of a patient toreach a first predetermined depth under the skin layer, and a sensorcoupled to the sensor introducer, and configured to reach a secondpredetermined depth under the skin layer, wherein the secondpredetermined depth is greater than the first predetermined depth.

The sensor introducer may be configured to pierce through the skin layerat a first velocity, and further, wherein the sensor is configured toreach the second predetermined depth at a second velocity, and where thefirst velocity may be greater than the second velocity.

The sensor introducer and the sensor may be coupled in a nestedconfiguration.

The sensor may be configured to reach the first predetermined depthsubstantially contemporaneously with the sensor introducer reaching thefirst predetermined depth.

In one aspect, the sensor may include a glucose sensor.

The sensor introducer may include a needle portion, where the needleportion may include a hollow segment, and at least a portion of thesensor may be substantially provided within the hollow segment of theneedle portion.

Further, the sensor introducer may be substantially entirely removedfrom the patient before the sensor reaches the second predetermineddepth.

The sensor may be in fluid contact with the patient's analyte at thesecond predetermined depth.

Additionally, the tissue trauma substantially at the secondpredetermined depth may be less than the tissue trauma substantially atthe first predetermined depth.

A method of analyte sensor insertion in yet another aspect may includepiercing a skin layer of a patient to a first predetermined depth, andinserting an analyte sensor through the pierced skin layer to positionthe sensor at a second predetermined depth which is greater than thefirst predetermined depth.

While the present invention has been described with reference to thespecific embodiments thereof, it should be understood by those skilledin the art that various changes may be made and equivalents may besubstituted without departing from the true spirit and scope of theinvention. In addition, many modifications may be made to adapt aparticular situation, material, composition of matter, process, processstep or steps, to the objective, spirit and scope of the presentinvention. All such modifications are intended to be within the scope ofthe claims appended hereto.

What is claimed is:
 1. A method of positioning an analyte sensor,comprising: positioning a portion of an analyte sensor removably coupledto a sensor introducer at a first depth below a skin surface at a firstvelocity; and positioning the portion of the analyte sensor without thesensor introducer at a second depth at a second velocity; wherein thecross-sectional area of an incision at the first depth made by thesensor introducer is greater than the cross-sectional area of theincision made by the analyte sensor at the second depth.
 2. The methodof claim 1, wherein positioning the portion of the analyte sensor at thefirst depth includes piercing the skin surface at a first angle relativeto the skin surface.
 3. The method of claim 2, wherein the first angleincludes one of a 90 degrees relative to the skin surface or less than90 degrees relative to the skin surface.
 4. The method of claim 1,wherein the first velocity and the second velocity are different, andfurther, wherein the first depth and the second depth are different. 5.The method of claim 1, wherein the first depth is not deeper than theepidermis.
 6. The method of claim 1, wherein the analyte sensorcomprises a plurality of electrodes including a working electrode,wherein the working electrode comprises an analyte-responsive enzyme anda mediator, and further, wherein at least one of the analyte-responsiveenzyme and the mediator is chemically bonded to a polymer disposed onthe working electrode.
 7. The method of claim 6, wherein at least one ofthe analyte-responsive enzyme and the mediator is crosslinked with thepolymer.
 8. A method, comprising: piercing a skin surface to a firstdepth at a first velocity to position a portion of an analyte sensor atthe first depth, wherein an incision at the first depth has a firstincision cross-sectional area; and displacing the portion of the analytesensor to a second depth at a second velocity, wherein an incision atthe second depth has a second incision cross-sectional area, wherein thefirst incision cross-sectional area is greater than the second incisioncross-sectional area.
 9. The method of claim 8, wherein tissue trauma atthe second depth is less than the tissue trauma at the first depth. 10.The method of claim 8, wherein the analyte sensor is in fluid contactwith interstitial fluid at the second depth.
 11. The method of claim 8,wherein the analyte sensor comprises a plurality of electrodes includinga working electrode, wherein the working electrode comprises ananalyte-responsive enzyme and a mediator, and further, wherein at leastone of the analyte-responsive enzyme and the mediator is chemicallybonded to a polymer disposed on the working electrode.
 12. The method ofclaim 11, wherein at least one of the analyte-responsive enzyme and themediator is crosslinked with the polymer.
 13. A method, comprising:actuating a sensor insertion device to incise a skin surface with asensor introducer and to insert a portion of an analyte sensor throughthe incised skin surface into subcutaneous tissue; wherein at least twodifferent selected velocities are used to incise the skin surface and toinsert the portion of the analyte sensor into the subcutaneous tissue;and further wherein the width of an incision created by incising theskin surface using the sensor introducer is greater than a width of asubsequent incision created within the skin surface incision by drivingthe portion of the analyte sensor into the subcutaneous tissue.
 14. Themethod of claim 13, wherein at least one velocity differs from a secondvelocity by about 25% to about 90%.
 15. The method of claim 13, whereina velocity to incise the skin surface is in the range from about 4 m/sto about 8 m/s.
 16. The method of claim 13, wherein a velocity to insertthe analyte sensor through the incised skin surface into subcutaneousadipose tissue is in the range from about 0.025 m/s to about 0.5 m/s.17. The method of claim 13, wherein the skin surface is incised to afirst depth and the analyte sensor is inserted to a second depth,wherein the second depth is greater than the first depth.
 18. The methodof claim 13, wherein the analyte sensor comprises a plurality ofelectrodes including a working electrode, wherein the working electrodecomprises an analyte-responsive enzyme and a mediator, and further,wherein at least one of the analyte-responsive enzyme and the mediatoris chemically bonded to a polymer disposed on the working electrode. 19.The method of claim 18, wherein at least one of the analyte-responsiveenzyme and the mediator is crosslinked with the polymer.